Characterizing linkage disequilibrium and evaluating imputation power of human genomic insertion-deletion polymorphisms

Abstract

BackgroundIndels are an important cause of human variation and central to the study of human disease. The 1000 Genomes Project Low-Coverage Pilot identified over 1.3 million indels shorter than 50 bp, of which over 890 were identified as potentially disruptive variants. Yet, despite their ubiquity, the local genomic characteristics of indels remain unexplored.ResultsHerein we describe population- and minor allele frequency-based differences in linkage disequilibrium and imputation characteristics for indels included in the 1000 Genomes Project Low-Coverage Pilot for the CEU, YRI and CHB+JPT populations. Common indels were well tagged by nearby SNPs in all studied populations, and were also tagged at a similar rate to common SNPs. Both neutral and functionally deleterious common indels were imputed with greater than 95% concordance from HapMap Phase 3 and OMNI SNP sites. Further, 38 to 56% of low frequency indels were tagged by low frequency SNPs. We were able to impute heterozygous low frequency indels with over 50% concordance. Lastly, our analysis also revealed evidence of ascertainment bias. This bias prevents us from extending the applicability of our results to highly polymorphic indels that could not be identified in the Low-Coverage Pilot.ConclusionsAlthough further scope exists to improve the imputation of low frequency indels, our study demonstrates that there are already ample opportunities to retrospectively impute indels for prior genome-wide association studies and to incorporate indel imputation into future case/control studies.

An integrative variant analysis pipeline for accurate genotype/haplotype inference in population NGS data

“…Similarly our imputation platform also provides opportunities to incorporate GLs for biallelic structural variants, copy number variants, and INDELs (Lu et al 2012) produced by other variant callers McKenna et al 2010;Albers et al 2011;DePristo et al 2011;Handsaker et al 2011). Nonetheless challenges remain; work on incorporating multiallelic SNPs as well as integration of polymorphic structural variants, copy number variants, and INDELs from low-coverage genomic data continues to be compelling.…”

Desaturase and elongase-limiting endogenous long-chain polyunsaturated fatty acid biosynthesis

“…rs174575 and rs174570 are within 600 and 6000 bp upstream from the FADS2 Indel, respectively [13, 34, 46]. In humans, common SNP variants are often found to follow Indels [61], suggesting that rs174575, rs174570 and/or rs1535 are tags for the functional genomic Indel that directly modulates binding at the nearby SRE. Whether or not the Indel is the functional element or it is nearby, genotypic variation controlling basal concentrations of 20:4n-6, its immediate precursor and its products, demonstrates in vivo that FADS2 protein(s) is (are) a major rate limiting enzyme for LCPUFA production.…”

Radiogenomics: A systems biology approach to understanding genetic risk factors for radiotherapy toxicity?

“…Small INDELs from 1-20,000 bp in length are relatively common in the genome and can be detected by NGS (104-106) although the presence of small-scale repeat sequences make the analysis a challenge (107). In all, 3.6 million INDELs have been described (88) which frequently show strong linkage disequilibrium with SNPs providing tags for imputation from GWAS (104, 108). Thus INDELs should be taken into consideration as potentially causative for the phenotype and lend themselves to retrospective analysis of GWAS.…”